The present invention relates to antibodies for diagnosis and treatment of neuropsychiatric diseases. The invention essentially relates to neuropsychiatric diseases, such as schizophrenia, depression or bipolar affective disorders. The present application focuses essentially on schizophrenia. However, the statements thus made also pertain generally to other neuropsychiatric diseases.
Schizophrenia is a neuropsychiatric disease likely to have heterogeneous causes. From studies on twins it has meanwhile become accepted that biological causes are responsible for the development of schizophrenia. In terms of neuropathology, patients with schizophrenia are characterized by an expansion of the third cerebral ventricle which is considered to be an unspecific sign of a loss of brain structure. Schizophrenia, at least one sub-group of schizophrenia, namely those with pronounced so-called negative symptoms, can be classified amongst the neurodegenerative diseases (J. Lieberman 1999, Biological Psychiatry 46: 729f).
To date, no diagnosis of schizophrenia or other neuropsychiatric diseases can be made on the basis of biological criteria. In order to determine a diagnosis, suitably trained physicians (psychiatrists, neurologists) interview for certain main psychiatric symptoms; this can be made more objective by means of so-called check lists. Unlike diseases in the area of internal medicine or neurology, the disease cannot be diagnosed by means of unambiguous blood or liquor tests or imaging procedures. This leads to some uncertainty in determining the diagnosis.
From WO 0026675 a generic method for diagnosis of neuropsychiatric diseases is known, in which the presence of polyglutamine-containing proteins in a tissue or body fluid sample of a patient is tested by means of an antibody that is directed against polyglutamine-containing protein domains. Further, WO 0026675 specifies that the neuropsychiatric diseases to be diagnosed with this method can be schizophrenia.
Polyglutamine-containing proteins are present in a plurality of neurodegenerative diseases, e.g. Huntington's disease or spinocerebellar ataxias. These diseases are characterized by increased occurrence of repeating glutamine residues in one or more proteins due to mutation, and are also referred to collectively as CAG repeat diseases since the DNA triplet, CAG, codes for glutamine.
In this context, for example, in Huntington's disease, a mutation in the human HD gene leads to an increase in the number of glutamine residues at the N-terminus of the huntingtin protein. Because of its erroneous amino acid sequence, the polyglutamine-rich mutant huntingtin tends to aggregate with other polyglutamine-rich huntingtin molecules. In the process, agglomerates are formed in the cellular nucleus of neurons that are associated with the fatal course of the disease. Similar sequence-related protein aggregations are thought to be responsible for the generation of disease-specific symptoms of other polyglutamine diseases.
The method known from WO 0026675 uses a monoclonal antibody (1C2) that is directed against polyglutamine-containing protein domains and is therefore not specific for schizophrenia. The method is only suitable for detecting polyglutamine-containing proteins. However, there is some doubt as to whether or not schizophrenia is even associated with the occurrence of polyglutamine-containing proteins. These doubts shall be elaborated in more detail below.
On the presumption—postulated in WO 0026675, but nevertheless incorrect—that schizophrenia is associated with the presence of polyglutamine-containing proteins, the known method could, thus, help in supporting a suspicion of schizophrenia that is based on a psychiatric diagnosis. However, diagnosis of schizophrenia through the use of this method alone is not feasible.